Departments of Neurology and Neurosurgery, Yale University School of Medicine, 15 York Street, LCI 710A, New Haven, CT, 06520, USA,
Neurocrit Care. 2014 Aug;21(1):43-51. doi: 10.1007/s12028-014-9970-2.
Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82 cm(3) treated with RP-1127 (glyburide for injection). In this secondary analysis, we tested the hypothesis that RP-1127 may be efficacious in preventing poor outcome when compared to controls.
Controls suffering large hemispheric infarction were obtained from the EPITHET and MMI-MRI studies. We first screened subjects for controls with the same DWI threshold used for enrollment into GAMES-Pilot, 82 cm(3). Next, to address imbalances, we applied a weighted Euclidean matching. Ninety day mRS 0-4, rate of decompressive craniectomy, and mortality were the primary clinical outcomes of interest.
The mean age of the GAMES cohort was 51 years and initial DWI volume was 102 ± 23 cm(3). After Euclidean matching, GAMES subjects showed similar NIHSS, higher DWI volume, younger age and had mRS 0-4-90% versus 50% in controls p = 0.049; with a similar trend in mRS 0-3 (40 vs. 25%; p = 0.43) and trend toward lower mortality (10 vs. 35%; p = 0.21).
In this pilot study, RP-1127-treated subjects showed better clinical outcomes when compared to historical controls. An adequately powered and randomized phase II trial of patients at risk for malignant infarction is needed to evaluate the potential efficacy of RP-1127.
恶性梗死的特征是脑水肿的形成，而医学治疗方法有限。临床前数据表明，SUR1-TRPM4 的抑制剂格列苯脲在预防水肿方面有效。我们之前报道了 GAMES-Pilot 研究的可行性，这是一项在高风险恶性梗死的 10 名患者中进行的双中心前瞻性、开放标签、IIa 期试验，这些患者基于扩散加权成像（DWI）阈值为 82cm³，接受 RP-1127（格列苯脲注射液）治疗。在这项二次分析中，我们测试了假设，即与对照组相比，RP-1127 可能在预防不良预后方面有效。
对照组患者来自 EPITHET 和 MMI-MRI 研究。我们首先筛选出与 GAMES-Pilot 研究相同的 DWI 阈值（82cm³）的对照组患者。然后，为了解决不平衡问题，我们应用了加权欧式匹配。90 天 mRS 0-4、去骨瓣减压术率和死亡率是主要的临床关注结局。
GAMES 队列的平均年龄为 51 岁，初始 DWI 体积为 102 ± 23cm³。经过欧式匹配后，GAMES 患者的 NIHSS 相似，DWI 体积更大，年龄更小，mRS 0-4-90%，而对照组为 50%，p = 0.049；mRS 0-3（40 对 25%；p = 0.43）和死亡率（10 对 35%；p = 0.21）也有类似的趋势。
在这项初步研究中，与历史对照组相比，接受 RP-1127 治疗的患者临床结局更好。需要进行一项足够大且随机的、针对恶性梗死高危患者的 II 期试验，以评估 RP-1127 的潜在疗效。
